Sex differences in hepatocellular carcinoma indicated BEX4 as a potential target to improve efficacy of lenvatinib plus immune checkpoint inhibitors.

Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer, and significant sex disparities have been observed in HCC. We aim to explore the potential sex-biased mechanisms involved in hepatocarcinogenesis. Methods: Based on TCGA data, we compared clinical features, genetic alterations, and immune cell infiltrations between male and female HCC patients. In addition, we performed sex-based differential expression analysis and functional enrichment analysis. Finally, GSE64041 dataset and another HCC cohort were engaged to validate our findings. Results: Significant differences of genetic alterations and TME were observed between male and female HCC patients. Enhanced metabolism of lipids was associated with hepatocarcinogenesis in men, while ECM-organization-related pathways were correlated to HCC development in women. BEX4 was upregulated in female but downregulated in male HCC patients, and was positively correlated with immune checkpoint molecules and infiltrated immune cell. These findings were further validated in dataset GSE64041 and our HCC cohort. More importantly, a negative correlation was found between BEX4 expression and lenvatinib sensitivity. Conclusion: Distinct biological processes were involved in sex-biased tumorigenesis of HCC. BEX4 can be targeted to improve the efficacy of lenvatinib plus immune checkpoint inhibitors.

AADAC protects colorectal cancer liver colonization from ferroptosis through SLC7A11-dependent inhibition of lipid peroxidation.

BACKGROUND: Oxidative stress is a highly active metabolic process in the liver, that poses great threats to disseminated tumor cells during their colonization. Here, we aimed to investigate how colorectal cancer (CRC) cells overcome lipid peroxidation to sustain their metastatic colonization in the liver. METHODS: Orthotopic colorectal liver metastasis (CRLM) and CRC liver colonization mouse models were constructed to determine the roles of lipid peroxidation and AADAC in CRC liver colonization. The levels of lipid peroxidation were detected in cells or tissues. AADAC overexpression in LMs and its clinical relevance were analyzed. The oncogenic role of AADAC in CRC liver colonization was evaluated in cell experiments. RESULTS: Compared with primary tumors (PTs), liver metastases (LMs) showed significantly lower glutathione to oxidized glutathione (GSH/GSSG) ratio and higher malondialdehyde (MDA) levels in CRLM patients and orthotopic mouse models. Inhibition of lipid peroxidation by liproxstatin-1 promoted CRC liver colonization in mouse models. RNA-seq results revealed AADAC as the most significantly upregulated lipid metabolism related gene in LMs compared with PTs. Analyses of datasets and patient and mouse model samples confirmed that AADAC was upregulated in LMs compared with PTs, and was correlated with poor prognosis. AADAC promoted cell proliferation, and facilitated liver colonization in a mouse model by reducing ROS accumulation, which led to lipid peroxidation and ferroptosis. Mechanistically, AADAC upregulated SLC7A11 by activating NRF2 to inhibit lipid peroxidation, thereby protecting metastatic cells from ferroptosis. CONCLUSIONS: AADAC protects metastatic CRC cells from ferroptosis by inhibiting lipid peroxidation in an SLC7A11-dependent manner, thus effectively promoting their metastatic colonization and growth in the liver. Together, our findings suggest that AADAC can act as a prognostic indicator and potential therapeutic target for CRLM.

Integrated bioinformatics analysis revealed the regulation of angiogenesis by tumor cells in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality, metastasis accounts for most of the cases. Angiogenesis plays an important role in cancer metastasis, but how tumor cells affect the function of endothelial cells by dictating their microRNA (miRNA) expression remains largely unknown. Differentially expressed miRNAs (DEMs) were identified through dataset downloaded from the Gene Expression Omnibus (GEO) database and analyzed by GEO2R. We then used online tools to obtain potential targets of candidate miRNAs and functional enrichment analysis, as well as the protein-protein interaction (PPI). Finally, the function of miR-302c-3p was validated through in vitro assay. In the current study, we found that HCC cells altered miRNA expression profiles of human umbilical vein endothelial cells (HUVECs) and miR-302c-3p was the most down-regulated miRNA in HUVECs when they were co-cultured with HCC-LM3 cells. Functional enrichment analysis of the candidate targets revealed that these genes were involved in epigenetic regulation of gene expression, in particular, cytosine methylation. In addition, PPI network demonstrated distinct roles of genes targeted by miR-302c-3p. Importantly, inhibition of angiogenesis, migration and permeability by the most down-regulated miR-302c-3p in HUVECs was confirmed in vitro. These findings brought us novel insight into the regulation of angiogenesis by HCC cells and provided potential targets for the development of therapeutic strategies.

Integrated bioinformatics analysis reveals role of the LINC01093/miR-96-5p/ZFAND5/NF-κB signaling axis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a significant health burden worldwide and its pathogenesis remains to be fully elucidated. One of the means by which long non-coding (lnc)RNAs regulate gene expression is by interacting with micro (mi)RNAs and acting as competing endogenous (ce)RNAs. lncRNAs have important roles in various diseases. The aim of the present study was to examine the potential roles of lncRNAs in HCC. The RNA expression profiles of 21 paired tissues of HCC and adjacent non-tumor tissues were obtained from the Gene Expression Omnibus database. The differentially expressed RNAs were analyzed using the DESeq package in R. Expression validation and survival analysis of selected RNAs were performed using Gene Expression Profile Interactive Analysis and/or Kaplan-Meier Plotter. The target genes of the miRNAs were predicted using lncBase or TargetScan. Functional analyses were performed using the Database for Annotation, Visualization and Integrated Discovery, and regulatory networks were determined using Cytoscape. Long intergenic non-protein coding RNA 1093 (LINC01093) was identified as one of the most significantly downregulated lncRNAs in HCC tissues. Downregulated expression of LINC01093 was associated with poor prognosis. A ceRNA network involving LINC01093, miR-96-5p and zinc finger AN1-type containing 5 (ZFAND5) was established. According to functional analyses, NF-κB signaling was implicated in the regulatory network for HCC. The present study revealed that a LINC01093/miR-96-5p/ZFAND5/NF-κB signaling axis may have an important role in the pathogenesis of HCC, and further investigation of this axis may provide novel insight into the development and progression of HCC.